An unexpected discovery

29 May 2014
By Susie Cooke

Somatic pseudogenes, such as this example of a gene called FOPNL (purple/pink shaded blocks), insert randomly into the cancer genome, in this case into the intron of another gene, SND1 (wavy blue lines).  The insertion has many of the same features as germline pseudogenes (these features are indicated by black arrows). These insertions are detectable as a characteristic pattern of split and paired reads in high-throughput sequencing data (shown above). Credit: doi:10.1038/ncomms4644

Somatic pseudogenes, such as this example of a gene called FOPNL (purple/pink shaded blocks), insert randomly into the cancer genome, in this case into the intron of another gene, SND1 (wavy blue lines). The insertion has many of the same features as germline pseudogenes (these features are indicated by black arrows). These insertions are detectable as a characteristic pattern of split and paired reads in high-throughput sequencing data (shown above). Credit: doi:10.1038/ncomms4644

The discovery of pseudogenes acquired during cancer development was one of those eureka moments the lucky among us get to experience in science.

Not, I hasten to add, because it is a discovery on a par with measuring the volume of complex objects (check out ‘eureka’ on Wikipedia if you’re not familiar with the story), but rather because it was a chance discovery made while doing something else entirely.

I was mapping genomic junctions in cancers – events where two pieces of DNA that are separate in normal cells have been linked together by cancer cells. One such junction had an unusual structure: of the two pieces of DNA being joined together, one had an additional alteration, with a feature called an intron (a non-functional segment of DNA), being removed.

DNA is a collection of gene templates that can be copied into RNA for use by the cell. A cell can make thousands of RNA copies of a gene and modify them in various ways, including removing introns. However, the machinery that carries out these modifications can’t do this to the original DNA template as it does not recognise the DNA. Except that what I was looking at appeared to be exactly that.

Announcing this unusual observation to our open-plan office resulted in a cluster of scientists puzzling over my computer screen. It was at this moment that Peter, our team leader and senior author of this work, walked in. After a quick look his instant (and arguably infuriating!) reaction was, “but you know what that is, don’t you?”. It turns out that a couple of years ago he’d realised that pseudogenes, which are familiar to geneticists as features arising during the evolution of the human genome, might also occur as part of the evolution and growth of cancer.

Pseudogenes arise when one of the gene copies a cell has made and modified is stably reincorporated back into the genome and passed on to subsequent generations. However, no one had actually seen this process occurring in cancer cells, until now. Turning to me, Peter said, “So now you’ve found one you need to check all the samples we’ve ever sequenced and see how many more there are…”.

Our paper ‘Processed pseudogenes acquired somatically during cancer development‘, published recently in Nature Communications, describes the analysis pipeline we developed to automate detection of these events, and their contribution to several common cancer types. This discovery, identifying a new mutational process in cancer, adds another piece to the puzzle of how cancers acquire the changes that turn them from normal healthy cells to aggressive and invasive tumours.

Susie Cooke is a former post-doc with the Cancer Genome Project. Her main research interest is characterising large-scale structural alterations of the cancer genome.

References

  • Cooke SL, et al. (2014) Processed pseudogenes acquired somatically during cancer development. Nature Communications. doi:10.1038/ncomms4644

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